EPIDIOLEX
Clinical safety rating: caution
Comprehensive clinical and safety monograph for EPIDIOLEX (EPIDIOLEX).
Cannabidiol is a cannabinoid with anticonvulsant properties. Its exact mechanism is unknown but may involve modulation of neuronal calcium channels, inhibition of adenosine reuptake, and agonism of 5-HT1A receptors.
| Metabolism | Primarily hepatic via CYP3A4 and CYP2C19; also glucuronidation via UGT1A7, UGT2B7, and UGT1A9. Active metabolite: 7-hydroxy-cannabidiol (7-OH-CBD). |
| Excretion | Cannabidiol (CBD) is primarily eliminated via fecal excretion (approximately 73-94% of the dose) as unchanged drug and metabolites, with renal excretion accounting for less than 5% of the dose. Biliary excretion contributes to fecal elimination. |
| Half-life | The terminal elimination half-life of cannabidiol following oral administration is approximately 56-61 hours in healthy volunteers and 31-40 hours in patients with epilepsy. This long half-life supports once-daily dosing for chronic conditions. |
| Protein binding | Cannabidiol is extensively bound to plasma proteins, primarily albumin, with a protein binding of approximately 94-99% (mean ~97%). |
| Volume of Distribution | The apparent volume of distribution (Vd/F) is approximately 20-30 L/kg (range: 17-40 L/kg) after oral administration, indicating extensive distribution into tissues. This high Vd reflects accumulation in adipose tissue and brain. |
| Bioavailability | Oral bioavailability of cannabidiol is low and variable, approximately 6-20% (mean ~13%) following a single oral dose, due to extensive first-pass metabolism. The oral solution formulation (Epidiolex) has a relative bioavailability approximately 4-5 times higher than that of oral capsules. |
| Onset of Action | Oral administration: Time to peak plasma concentration (Tmax) is 2.5-5 hours. Clinical effects (e.g., seizure reduction) are typically observed within 1-2 weeks of initiating therapy, although earlier effects may occur. |
| Duration of Action | Steady-state concentrations are achieved within approximately 1 week (5 half-lives). The pharmacodynamic duration supports once-daily dosing, with persistent anticonvulsant effects throughout the dosing interval. |
Initial 2.5 mg/kg orally twice daily; after 1 week, increase to 5 mg/kg twice daily; may titrate to 10 mg/kg twice daily based on tolerability and efficacy. Maximum dose: 20 mg/kg daily.
| Dosage form | SOLUTION |
| Renal impairment | No dose adjustment required based on renal function; pharmacokinetics not significantly affected by mild to moderate renal impairment, data lacking for severe impairment (CrCl <30 mL/min). |
| Liver impairment | For Child-Pugh A: 2.5 mg/kg twice daily (50% of max dose); Child-Pugh B: 1.25 mg/kg twice daily (25% of max dose); Child-Pugh C: not recommended. |
| Pediatric use | Age 1 year and older: same weight-based dosing as adults (initial 2.5 mg/kg twice daily, titrate to 5-10 mg/kg twice daily); for Dravet or Lennox-Gastaut syndromes, maximum 20 mg/kg daily. |
| Geriatric use | No specific dosing guidelines; use caution due to potential increased sensitivity, hepatic impairment, and concurrent medications; start at low end of dosing range and titrate slowly. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for EPIDIOLEX (EPIDIOLEX).
| Breastfeeding | CBD is excreted in human milk; however, the milk-to-plasma ratio (M/P) has not been established. A case report detected CBD in breastmilk at low concentrations (approx. 0.02% of maternal weight-adjusted dose). Due to limited data and potential for adverse effects on the nursing infant, caution is advised. Consider alternatives or temporarily discontinue breastfeeding during therapy. |
| Teratogenic Risk | In animal studies, cannabidiol (CBD) has demonstrated developmental toxicity including increased fetal mortality, reduced fetal body weight, and increased incidence of skeletal variations at doses below the maximum recommended human dose. No adequate and well-controlled studies in pregnant women exist. Based on animal data, there is a potential risk for adverse developmental outcomes including neural tube defects and fetal growth restriction. Use during pregnancy only if the potential benefit justifies the potential risk to the fetus. |
■ FDA Black Box Warning
No boxed warning.
| Serious Effects |
["Hypersensitivity to cannabidiol or any component of the formulation."]
| Precautions | ["Hepatocellular injury: Elevations of liver transaminases (ALT/AST) and total bilirubin; monitor LFTs before and during treatment.","Somnolence and sedation: Commonly occurs, especially with higher doses.","Suicidal thoughts and behavior: Increased risk of suicidal ideation and behavior in patients taking antiepileptic drugs.","Withdrawal: Abrupt discontinuation may increase seizure frequency; taper gradually.","Drug interactions: Inhibits CYP2C19, CYP3A4, and UGT enzymes; may increase levels of clobazam, valproate, and other drugs."] |
| Food/Dietary | Grapefruit and grapefruit juice may increase cannabidiol exposure; avoid concurrent use. High-fat meals increase absorption; advise consistent timing with meals to minimize variability. |
Loading safety data…
| Fetal Monitoring | Monitor for somnolence, sedation, hepatotoxicity (elevated transaminases, bilirubin), and suicidal thoughts/behavior. During pregnancy, monitor fetal growth via ultrasound as animal studies showed reduced fetal weight. Assess liver function tests at baseline and periodically. No specific fetal monitoring required beyond standard prenatal care. |
| Fertility Effects | Animal studies have shown reduced fertility in male and female rats at doses equivalent to the maximum recommended human dose. Effects included decreased sperm count, motility, and altered estrous cycles. In humans, no formal fertility studies have been conducted; however, potential for reversible impairment of fertility exists. |
| Clinical Pearls | Epidiolex (cannabidiol) is a first-in-class antiepileptic for Dravet and Lennox-Gastaut syndromes. Monitor hepatic function at baseline and periodically due to risk of transaminase elevation. Titrate slowly to minimize diarrhea and somnolence. Avoid concurrent use with clobazam without dose adjustment due to increased N-desmethylclobazam levels. Drug-drug interactions via CYP3A4 and CYP2C19 inhibition. |
| Patient Advice | Take with food to reduce gastrointestinal upset. · Store at room temperature; protect from light. · Do not stop abruptly; taper to avoid withdrawal seizures. · Report signs of liver injury: jaundice, dark urine, nausea, vomiting. · May cause somnolence; avoid driving until effects known. |